Fibrin Sealants in Dura Sealing: A Systematic
Literature Review
Felice Esposito1☯*, Filippo Flavio Angileri1☯, Peter Kruse2☯, Luigi Maria Cavallo3☯,
Domenico Solari3☯, Vincenzo Esposito4☯, Francesco Tomasello1☯, Paolo Cappabianca3☯
1 Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, Division of Neurosurgery, Università degli Studi di Messina, Messina, Italy, 2 Independent medical advisor, Cervignano del Friuli, Italy, 3 Department of Neurosciences and Odontostomatological and Reproductive Sciences, Division of Neurosurgery, Università degli Studi di Napoli Federico II, Naples, Italy, 4 Division of Neurosurgery, Università degli Studi di Roma Sapienza, Rome, Italy
☯ These authors contributed equally to this work. *fesposito@unime.it
Abstract
Background
Fibrin sealants are widely used in neurosurgery to seal the suture line, provide watertight closure, and prevent cerebrospinal fluid leaks. The aim of this systematic review is to sum-marize the current efficacy and safety literature of fibrin sealants in dura sealing and the pre-vention/treatment of cerebrospinal fluid leaks.
Methods
A comprehensive electronic literature search was run in the following databases: Cochrane Database of Systematic Reviews, Cochrane Central Resister of Controlled Trials, clinical-trials.gov, MEDLINE/PubMed, and EMBASE. Titles and abstracts of potential articles of interest were reviewed independently by 3 of the authors.
Results
A total of 1006 database records and additional records were identified. After screening for duplicates and relevance, a total of 78 articles were assessed by the investigators for eligi-bility. Thirty-eight were excluded and the full-text of 40 articles were included in the qualita-tive synthesis. Seven of these included only safety data and were included in the safety assessment. The remaining 33 articles included findings from 32 studies that enrolled a total of 2935 patients who were exposed to fibrin sealant. Among these 33 studies there were only 3 randomized controlled trials, with the remaining being prospective cohort analy-sis, case controlled studies, prospective or retrospective case series. One randomized con-trolled trial, with 89 patients exposed to fibrin sealant, found a greater rate of intraoperative watertight dura closure in the fibrin sealant group than the control group (92.1% versus 38.0%, p<0.001); however, post-operative cerebrospinal fluid leakage occurred in more fibrin sealant than control patients (6.7% versus 2.0%, p>0.05). Other clinical trials evalu-ated the effect of fibrin sealant in the postoperative prevention of cerebrospinal fluid leaks.
a11111
OPEN ACCESS
Citation: Esposito F, Angileri FF, Kruse P, Cavallo LM, Solari D, Esposito V, et al. (2016) Fibrin Sealants in Dura Sealing: A Systematic Literature Review. PLoS ONE 11(4): e0151533. doi:10.1371/journal. pone.0151533
Editor: Giovanni Grasso, Universita degli Studi di Palermo, ITALY
Received: October 28, 2015 Accepted: February 28, 2016 Published: April 27, 2016
Copyright: © 2016 Esposito et al. This is an open access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability Statement: All data are available in publications searchable through Cochrane Database of Systematic Reviews (http://www.cochrane.org/ cochrane-reviews), Cochrane Central Register of Controlled Trials, MEDLINE/PubMed (1950 to present [2015 June]),www.clinicaltrials.gov
(searched for on-going trials or other concluded trials), and EMBASE via Ovid (1974 to present [2015 June]).
Funding: Dr. Felice Esposito received an unrestricted research grant from Baxter Italy and has given some didactic presentations on Dural Sealing methods. Dr. Paolo Cappabianca received an
These were generally lower level evidence studies (ie, not prospective, randomized, con-trolled trials) that were not designed or powered to demonstrate a significant advantage to fibrin sealant use. Two small case series studies evaluated the effect of fibrin sealants in persistent cerebrospinal fluid leak treatment, but did not establish firm efficacy conclusions. Specific adverse reports where fibrin sealants were used for dura sealing were limited, with only 8 cases reported in neurosurgical procedures since 1987 and most reporting only a speculative relationship/association with fibrin sealant exposure.
Conclusions
A major finding of this systematic literature review is that there is a paucity of randomized studies that have evaluated the effectiveness and safety of fibrin sealants in providing intraoperative watertight dura closure and post-operative cerebrospinal fluid leakage. Among the limited studies available, evidence from a single randomized, controlled trial indi-cates that fibrin sealants provide a higher rate of intraoperative watertight closure of the dura suture line than control, albeit with a higher rate of postoperative cerebrospinal fluid leakage. Evidence from non-randomized, controlled trials suggests that fibrin sealants may be effective in preventing cerebrospinal fluid leaks with an acceptable safety profile. There is a substantial need for randomized, controlled clinical trials or well-designed prospective observational trials where the conduct of a randomized trial is not feasible to fully assess the impact of fibrin sealant utilization on the rates of intraoperative dura closure, postopera-tive cerebrospinal leakage, and safety.
Introduction
In neurosurgery, disruption of the arachnoid and dura allows cerebrospinal fluid (CSF) to flow
or leak into an extradural space—an event that may lead to life-threatening complications such
as infection and pneumocephalus. Reported incidences of CSF leaks vary from 0.8% to 13%
depending on type of surgery and other factors [1–4]. The relative risk of developing
meningi-tis in patients with postoperative CSF leak has been reported to be more than 10 [5].
Neurosurgeons aim to reduce the risk of CSF leaks by meticulous suturing of the dura, fibrin sealants, and by the use of dural patches/grafts when possible. In other cases, such as endonasal endoscopic skull base surgery, primary suturing of the dura mater may be very difficult or even
impossible to achieve [6–11]. With increased intracranial pressure (>20 cm H2O), CSF may
leak through even small suture holes causing a persistent CSF leak. To minimize the risk of such CSF leaks, new approaches have been applied to provide a watertight closure of the dural incision/lesion; one such treatment modality is to use a fibrin sealant (FS) directly on the suture line to seal the suture holes.
Fibrin sealants are commercially available products that contain two main active ingredi-ents, fibrinogen and thrombin (human/animal/recombinant origin), that when mixed form a
fibrin clot [12]. These products are used to seal biological tissues, either as two component (ie,
fibrinogen and thrombin) liquid glue or as a two component dry patch. Liquid glue
formula-tions include Tisseel1or Tissucol™ (Baxter, Deerfield, IL, USA), Evicel1(Ethicon US, LLC),
and dry patch products such as Tachosil1(Baxter, Deerfield, IL, USA) and Tachocomb1(CSL
Behring, Tokyo, Japan) [12]. Among these products, Tisseel / Tissucol is one of the first fibrin
sealants and has been on the market over 30 years—it was first introduced to the European
unrestricted research grant from Baxter Italy and has given some didactic presentations on Dural Sealing methods. Dr. Peter Kruse was paid for this structured literature review as an independent clinical consultant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: Dr. Felice Esposito received an unrestricted research grant from Baxter Italy and has given some didactic presentations on Dural Sealing methods. He has no other conflicts of interest. Dr. Paolo Cappabianca received an unrestricted research grant from Baxter Italy and has given some didactic presentations on Dural Sealing methods. He has no other conflicts of interest. Dr. Peter Kruse was paid for this structured literature review as an independent clinical consultant. He has no other conflicts of interest. This does not alter the authors’ adherence to PLOS One policies on sharing data and materials.
market in 1978. Tisseel has two main active component groups: 1) Human fibrinogen, syn-thetic aprotinin (anti fibrinolytic) and Factor XIII and 2) Human thrombin and calcium
chlo-ride [9]. When the two groups are mixed and applied to tissue, the fibrinogen and thrombin
lead to generation of a fibrin clot that will adhere to tissue and have haemostatic (cease
bleed-ing) and adhesive (seal and act as a bio glue) capacities [13].
The haemostatic effectiveness of using a fibrin sealant in surgery has been well established in a Cochrane review establishing its reduction of both postoperative blood loss and
periopera-tive exposure to allogeneic red blood cell transfusion [14]. The non-blood compartment air
tight and water tight sealing effects of fibrin sealants have been studied in randomized con-trolled trials of many types of surgery. These include sealing of intestinal anastomosis and
pre-venting anastomotic leaks [12,15–17], reduction of alveolar air leaks after pulmonary surgery
[18], prevention of urethrocutaneous fistula after hypospadias repair [19], and in prevention of
pancreatic fistula [20] although an earlier randomized trial did not report this same effect [21].
Fistulae sealing represents a therapeutic use of fibrin sealants with studies reporting fistulae
closure in perianal/anal fistulaes [22,23], complex anal fistulae [24,25], and obstetrical
vesico-vaginal fistulaes [26].
In patients undergoing neurosurgical procedures, fibrin sealant properties of tissue adhe-sion, sealing, and bioabsorption potentially provide logical and clinically relevant benefits in where there is a need for effective dura mater sealing, prevention of perioperative acute CSF leakage, and/or treatment of persistent postoperative CSF leakage. The aim of this systematic review is to evaluate and summarize the current dura sealing efficacy and safety literature of fibrin sealants. This information will provide guidance as to whether the clinical efficacy and safety data for fibrin sealants support their use in dura sealing, either to prevent acute CSF peri-operative leaks in patients following neurosurgery or to prevent/treat persistent CSF postopera-tive/post-instrumentation leaks in patients undergoing neurologic or spinal procedures.
Methods
Search Strategy
PRISMA recommendations and criteria for a structured literature search and review were
fol-lowed [27]. An extensive systematic literature search was performed by an independent
clini-cian (PK) of the following electronic databases: Cochrane Database of Systematic Reviews (http://www.cochrane.org/cochrane-reviews), Cochrane Central Register of Controlled Trials,
MEDLINE/PubMed (1950 to present [2014 May]),www.clinicaltrials.gov(searched for
on-going trials or other concluded trials), and EMBASE via Ovid (1974 to present [2014 May]). For the MEDLINE and EMBASE searches, a wide variety of Medical Subject Headings (MeSH) have been used in key papers, therefore, exploded MeSH terms were used to ensure that all the appropriate papers were captured. The main search terms used to capture all the
studies available in MEDLINE and EMBASE are summarized inTable 1. The Cochrane Library
was searched using the search terms“fibrin sealant” or “cerebrospinal fluid.” For thewww.
clinicaltrials.govsearch, the broad search terms of“dura”, “fibrin sealant”, or “CSF leak” were used to identify completed or ongoing clinical trials evaluating the use of fibrin sealants in dura sealing.
Article Eligibility and Selection
Two physicians (FE and PK) scanned independently the retrieved articles’ titles and abstracts
for potential relevance and review inclusion eligibility. To be included, the article had to meet
strict criteria, as listed inTable 2, with the search and inclusion criteria primarily targeting
fibrin sealants used intraoperatively during neurosurgical procedures to prevent and/or treat CSF leaks. If only a few or no randomized controlled trials were identified, lower evidence level
reports (as defined inTable 3[28]) were allowed for an evaluation of efficacy provided that the
scope of the research was to evaluate the effect of fibrin sealants in dura sealing. The results of the two independent searches were matched in order to find the common results; the two phy-sicians reviewed the unmatched findings once more, in order to check if they met the inclusion
Table 1. Search Strategy for the MEDLINE/PubMed Database.
Number Searches
Identification of procedures and treatment target (CSF leak):
1 Neurosurgical Procedures [MeSH]
2 Neurosurgery [MeSH]
3 Cerebrospinal Fluid [MeSH]
4 Cerebrospinalfluid leak [MeSH]
5 cerebrospinal
6 cerebrospinalfluid
7 cerebrospinalfluid leak
8 dura mater
9 spinal puncture
10 spinal tap
11 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8
OR #9 OR #10 Identification of relevant fibrin sealants:
12 Fibrin Tissue Adhesive [MeSH]
13 fibrin adhesive 14 fibrin glue 15 fibrin seal 16 biological glue 17 biological seal 18 beriplast 19 biocol 20 collaseal 21 crosseal 22 evicel 23 hemaseal 24 omrixil 25 quixil 26 tachocomb 27 tachosil 28 tisseel 29 tissel 30 tissucol 31 transglutine 32 vivostat 33 #12 OR #13 OR. . .. . ...#32
Filter identification
34 animals [mh] NOT humans [mh] Final search
35 #11 AND #33 NOT #34
Table 2. Article Inclusion and Exclusion Criteria.
Inclusion Criteria Exclusion Criteria
Types of Studies Randomized controlled trials evaluating the efficacy of fibrin sealants in dura sealing. Non-randomized, controlled trials reporting efficacy were allowed provided that the scope of the research was to evaluate the effect offibrin sealants in dura sealing.
Minor case series/case reports with<20 patients.
All evidence levels, including case reports, that including safety data were acceptable for safety analysis inclusion.
Case series where different surgical techniques (including technical notes) are compared rather than the potential effects offibrin sealants.
Cost data reports without efficacy or safety data
Reviews, editorials, opinions, comments, and letters without original data.
Non-clinical (ie, experimental, animal, or in vitro) studies. Clinical trials with major quality issues and a high risk of bias were excluded from efficacy analysis, but could be included in safety analyses.
Types of Participants Patients (irrespective of age, sex or race) who: a) had undergone neurosurgical intervention of the brain or spine wherefibrin sealants had been used to seal dura in order to treat acute CSF leaks and/or to prevent CSF leaks
Patients with spontaneous or trauma-related CSF leaks.
or presented with persistent CSF leaks after neurosurgical procedures where conservative treatment had failed and where attempts to close the CSF leak usingfibrin sealants had been done
Patients wherefibrin sealant was used for haemostatic effect only.
or had spinal tap procedures with persistent CSF leaks. Types of
Interventions
Fibrin sealant either as liquid glue (drops or spray) or solid dry patch applied to: a) acute CSF leak after surgery as an add-on treatment covering the suture lines
Fibrin sealants mixed with other products such as bone chips/powder, hydroxyapatite etc.
b) acute CSF leak from dural patch of autologous fascia, pericranium or collagen-based dura substitute to cover the suture lines and patch.
Comparisons of differentfibrin sealant application methods.
c) persistent CSF leak after neurosurgical procedures and spinal puncture
Interventions wherefibrin sealant is not applied on or close to dura/dura grafts or suture lines involving dura to provide dura sealing.
Reports on the sole use of autologous/homemadefibrin sealants (non-standardized product characteristics). Types of comparators Placebo (sham) or nofibrin sealant treatment (just sutures). Studies where different patches/dura substitutes are
compared andfibrin sealants are used as the standard of care.
Medical treatment with acetazolamide.
Conservative treatment with persisting CSF leak Types of Efficacy
Outcome Measures
Could include (but not limited to): 1. After Surgery: a) acute CSF leaks (preferably after Valsalva maneuver to increase intracranial pressure); b) Early (1 week) persistent CSF leaks (β2-transferrin, computed tomography or magnetic resonance imaging); or c) Late (>4 weeks) persistent CSF leaks (β2-transferrin, computed tomography or magnetic resonance imaging).
2. After CSF Leak: a) the number of patients with effective closure of the CSF leak
Safety Outcome Measures
Could include (but not limited to):
Mortality.
Overall incidence of serious adverse events (quantitative). Overall incidence of adverse events related tofibrin sealants (quantitative).
Qualitative assessment of specific adverse events/serious adverse events related to use offibrin sealants.
Reoperation rate due to CSF leaks. doi:10.1371/journal.pone.0151533.t002
eligibility criteria. No cases of further disagreement between the two searching physicians occurred. Should any disagreement occurred, the relative articles would have been omitted from the analysis.
Among the identified articles meeting the selection criteria, full versions were used for data analysis and a secondary search of the listed citations was performed to ensure that all relevant publications were included. English-language publications were the primary focus, although studies in Italian and German were also assessed for potential importance/relevance with those reporting adverse events being translated (if the English abstract was not sufficient or available) and included in the safety analysis.
Data Appraisal and Extraction
The following data were extracted from each identified publication: trial characteristics includ-ing its design and outcome measures, settinclud-ing, location of care, and country; participant descrip-tions including sample size, age, sex, disease, and surgical procedure; intervention information including the type and brand of fibrin sealant used and, if comparator used, the type and brand; and details of study efficacy and/or safety results.
Results
Characteristics of Included Studies
The MEDLINE/PubMed and EMBASE literature searches identified a total of 1004 potential
citations with 3 citations identified through thewww.clinicaltrials.govsearch: no citations were
identified through the search of the Cochrane Library. Of the 3 citations identified through the clinicaltrials.gov site at the time of the literature review, results were posted for one study
(NCT00681824 [29]), one study was listed as completed without posted results (NCT01355627
[30]); and a citation (NCT01174992 [31]) with results found in a European Medicines Agency
Table 3. Defined Levels of Evidence in Literature Search Articles. 1a Systematic reviews (with homogeneity) of randomized controlled trials 1a- Systematic reviews of randomized trials displaying worrisome heterogeneity 1b Individual randomized controlled trials (with narrow confidence interval) 1b- Individual randomized controlled trials (with a wide confidence interval) 1c All or none randomized controlled trials
2a Systematic reviews (with homogeneity) of cohort studies
2a- Systematic reviews of cohort studies displaying worrisome heterogeneity 2b Individual cohort study or low quality randomized controlled trials (<80% follow-up)
2b- Individual cohort study or low quality randomized controlled trials (<80% follow-up / wide confidence interval)
2c “Outcomes” research; ecological studies
3a Systematic reviews (with homogeneity) of case-control studies
3a- Systematic reviews of case-control studies displaying worrisome heterogeneity 3b Individual case-control study
4 Case-series (and poor quality cohort and case-control studies)
5 Expert opinion without explicit critical appraisal, or based on physiology, bench research or“first principles”
Based on data from the Oxford Centre for Evidence-based Medicine [28], which is available at:http://www. cebm.net/index.aspx?o=1025
report [24]. The flow chart of the literature search and the citation selection, review, and
inclu-sion and excluinclu-sion process are illustrated inFig 1.
After the application of methods to remove 309 duplicate references (Reference Manager Profession, Version 12, Thomson Reuters and manual screening), a total of 697 citations remained. The abstracts of these citations were screened for inclusion and exclusion criteria and relevance, with 620 of these excluded as they did not cover the subject of the literature review. The full-text of the remaining 78 papers were reviewed and, of these, 40 met the a priori defined selection criteria with 33 meeting that for efficacy and some of these reporting on
safety. Two of the 33 papers reported on patients enrolled in a single trial [10,11]. Seven papers
contained specific safety reporting on fibrin sealant use in the predefined indication of
neuro-surgery for dura sealing. The citations were evaluated for their levels of evidence (Table 4) [28].
Three of the studies were randomized controlled trials of evidence levels 1b to 2 [24,29,32]
with the remaining being retrospective case series or cohort studies of evidence levels 2b to 4. Among the reviewed citations, a total of 2935 participants were exposed to fibrin sealants. Details of the study designs and participants, interventions, comparisons, outcome measures,
and authors’ conclusions are summarized for each trial inTable 5. By study type, 249
partici-pants were exposed to liquid fibrin sealants in 2 of the 3 randomized controlled trials [24,29].
A total of 126 participants were exposed to fibrin sealants in the remaining randomized
con-trolled trial [32] and one prospective cohort study [33]. In 2 case controlled studies [34,35],
Fig 1. PRISMA Flow Diagram of the Selection Process to Identify Studies for Review. doi:10.1371/journal.pone.0151533.g001
167 participants were exposed fibrin sealants, with the remaining 25 case series analyses report-ing on the remainreport-ing 2393 participants.
Notably, one case series citation by Cappabianca and colleagues of 50 subjects exposed to fibrin sealant, 40 were evaluated for postoperative CSF leak efficacy information: 10 subjects
were evaluated for treatment of persisting CSF leak efficacy [42]. Although the 10 subject
evalu-ation did not meet our literature search criteria, the informevalu-ation from this case series
subpopu-lation was included for completeness [42].
Fibrin Sealant Efficacy and Safety in Randomized Controlled Trials
As detailed inTable 6, the quality of each of the 3 randomized controlled trials [24,29,32]
var-ied in their level of evidence. The largest trial by Green and colleagues was conducted under the regulatory requirements for obtaining an indication in the European Union and was
pre-sented with an overall high study quality [24]. The remaining 2 randomized controlled trials
had small numbers of participants [29,32]. The one trial posted on clinicaltrials.gov
(NCT00681824 [29]), a pilot study to investigate the efficacy and safety of fibrin sealant
(Tis-seel) for use in posterior fossa surgery as an adjunct to dura and dura substitute sutures in pre-venting postoperative CSF leakage, was performed without any formal sample size calculation.
Limitations to the trial by Nakamura and colleagues [32] include its limited number of spinal
patients with an a priori sample size calculation and use of a pseudo randomization (clinical chart number system), which may have resulted in the trial being underpowered and having bias. These design and power limitations limit the ability to draw conclusions of efficacy from
their findings [32].
Efficacy and Safety of Fibrin Sealants, by Indication
The following subsections describe the strength of the overall evidence for the efficacy and safety of fibrin sealants in the prevention and/or treatment of acute or persistent CSF leaks, by these indications.
Treatment of acute (intraoperative) CSF leaks. One of the 3 randomized controlled trials
was designed to evaluate the efficacy and safety of a liquid fibrin sealant containing both thrombin and fibrinogen as an adjunct to dura sutures in patients undergoing elective cranial surgery (supratentorial/posterior fossa) who experienced a CSF leak after primary suture
clo-sure of the dura mater [24]. This clinical trial [24], which was identified from the clinicaltrials.
gov website, was used to submit data to the European Medicines Agency (EMA) to obtain the
Table 4. Literature Search: Summary of Levels of Evidence of the Included Studies. Level of
evidence [28]
Trial type Originally selected
studies
Studies included
Total number of patients in studies exposed tofibrin sealant
I Meta-analysis 0 0 0
Ib—Ib- Randomized controlled trial 2 2 123
II Prospective cohort studies / randomized controlled trial with quality issues
2 2 126
III Case-control studies 2 2 167
IV Prospective and retrospective case series 27 26 2519
Total - 33* 32* 2935
Note: multiple publications addressing data from the same study are counted once:
*The total of included studies for efficacy and safety is 32, two studies are reporting on the same patients [10,11]. doi:10.1371/journal.pone.0151533.t004
Table 5. Litera ture S earch: Sum mary of Stud ies with Re sults on Effica cy an d Safety. Author, year Study design Intervention comparison Population Total number of patients Patients exposed to fi brin sealant Ef fi cacy (primary endpoint in bold if stated in paper) Safety Author conclusions Evidence level Treatment of acute (intraoperative) cerebrospinal fl uid (CSF) leaks Green, et al [ 24 ] / NCT 01174992 [ 31 ] Randomized controlled trial Fibrin sealant (Evicel) OR Sutures (Control) (2:1 random) 18 years, undergoing elective craniotomy or craniectomy for pathological processes in the posterior fossa or in the supratentorial region and who were demonstrated to have persistent CSF leakage following primary attempt at suture closure of the dural incision 139 (89:50) 89 Intraoperative watertight dura closure was observed in a greater proportion of fibrin sealant-treate d than control group subjects (92.1% [82/89] versus 38.0% [19/50] of subjects respectively , p< 0.001) Post-operative CSF leakage after treatment occurred in 6.7% (6/89) of fibrin sealant and 2.0% ((1/ 50) of control group patients. One subject in each group developed meningitis The incidence of adverse events was comparable: 64.0% in fibrin sealant group versus 62.0% in control group Superiority of fibrin sealant over sutures in establishing intraoperative watertight closure of the dural incision was demonstrated. Post-operative CSF leaks was slightly higher in the fibrin sealant group. General safety (adverse events) was comparable 1b Hobbs 2011 [ 36 ] Retrospective case series If intraoperative CSF leak: fibrin sealant (Tisseel) +Spongostan + fibrin sealant + Spongostan followed by packing of the sphenoid sinus. No comparison Patients undergoing pituitary surgery procedures (96 primary procedures and 24 revisions) with intraoperative CSF leaks 120 28 28/120 intra operative CSF leaks were treated with the intervention. All intra operative leaks were managed using the fibrin sealant and gelatin sponge technique. One patient (3.6%) had a CSF leak that continued post-operatively that required a post-operative ventriculoperitone al shunt with the CSF leak subsequently resolving One case of aseptic meningitis Simple conservative technique with low incidence of postoperative CSF leak 4 Prevention of postoperativ e CSF leaks clinicaltrials. govNCT 00681824 [ 29 ] Randomized Controlled Pilot study Fibrin sealant (Tisseel) plus Standard of care OR Control (Standard of Control only) closure of dura defect with suture + patch (autologous fascia, pericranium or collagen based dura substitute) Age 3 years, undergoing elective craniotomy / craniectomy for pathological processes in the posterior fossa that resulted in dura defects requiring dura substitution for closure 62 with additional 13 "run in" patients 34 Incidence of CSF leakage observed 33 days after surgery (computed tomography/ magnetic resonance imaging/clinic al) was 78% in the fibrin sealant group compared with 74% in the control group (p = 0.72). Surgical revisions occurred in 3 vs. 0%, and surgical site infection in 2 vs. 0% (fi brin sealant vs. control, respectively ) Serious adverse events were reported in 21% vs. 14% and other adverse events in 70 vs. 71% (fi brin sealant vs. control, respectively) Fibrin sealant was not found to be superior in preventing CSF leakage postsurgery when compared with suture/patch. Safety, albeit not detailed, seemed comparable in the 2 groups 1b-Nakamura 2005 [ 32 ] Randomized controlled trial Group 1: Suture + Goretex; Group 2: Regimen 1 + fibrin sealant autologous; Group 3: Regimen 1 + fibrin sealant (Bolheal) Patients with spinal cord tumors and related illnesses undergoing spinal surgery 39 26 (13
autologous fibrin sealant;
13 fibrin sealant) Primary endpoint was drain output with no statistical difference between autologous fibrin sealant and fibrin sealant. No postsurgical CSF leak was observed in any of the patients in the 3 groups No complications observed and no adverse events reported No de finitive CSF leaks were observed in any group 2b (Continued )
Table 5. (Continued ) Author, year Study design Intervention comparison Population Total number of patients Patients exposed to fi brin sealant Ef fi cacy (primary endpoint in bold if stated in paper) Safety Author conclusions Evidence level Than 2008 [ 33 ]
Prospective cohort (polyethylene glycol) Retrospective control
(fi brin sealant) Polyethylene glycol versus fibrin sealant Patients undergoing cranial posterior fossa surgery 200 100 In the PEG group, two of 100 (2%) patients developed CSF leak postoperatively compared with 10 of 100 (10%) patients in fibrin sealant group (p = 0.03) There were no signi ficant differences in the rates of pseudo-meningocele, meningitis, or other postoperative interventions Polyethylene glycol dural sealant to the closed dural edges may be effective at reducing incisional CSF leak after posterior fossa surgery 2b-Tamasauskas 2008 [ 34 ] Case control study Method 1: Packing the sella and sphenoidal sinus: autologous fat and restoring the bone defect of the sella with autologous bone OR Method 2 (fi brin sealant): Multilayer sella closing using oxidized cellulose (Surgicel) and fibrin sealant based collagen fleece (Tachosil) Patients undergoing trans-sphenoid al operations for pituitary adenoma that developed intraoperative CSF leak 313 (58 with intra-operative CSF leak) 29 3/29 (10%) developed postoperative CSF leak with Method 1 compared with 0 with Method 2 (fi brin sealant) Hypopituitarism (1 versus 0), Sphenoidal sinusitis (2 versus 0), Permanent diabetes insipidus (2 versus 1), Paresis n. oculomotorius (1 versus 0), and Intraventricular haemorrhage (0 versus 1) when comparing number of cases with Method 1 versus Method 2 (fi brin sealant) Multilayer sella closing using oxidized cellulose (Surgicel) and fibrin sealant based collagen fleece appeared to be the most reliable one, as no postoperative CSF leakage applying this technique was observed 3b Yoshimoto 1997 [ 35 ] Case control study Case: Suture + fibrin sealant (Bolheal / Veriplast P). Control: Suture Patients mean age of 60 years undergoing craniotomy for unruptured aneurysm 183 138 CT veri fi ed fl uid collection occurred in 19/ 45 patients (42%) without fibrin sealant and in 36/ 138 patients (26%) with fibrin sealant, (p < 0.05). All fluid collections detected were transient and no patient required second surgery due to CSF leak No infections, including meningitis and no other adverse effects were detected Fibrin sealant is a useful surgical tool for the prevention of postoperative extradural fluid collection through the dural sutures 3b Cappabianca 2004 [ 37 ] Retrospective cohorts Group 1: Fibrin sealant (Tissucol); Group 2: Collagen fleece; Group 3: Fibrin sealant + Collagen fleece Patients undergoing sellar repair after endoscopic endonasal transsphenoidal surgery. 242 29 Group 1 (fi brin sealant, n = 16): CSF leaks occurred in 2/16 (12.5%) patients and 6/16 patients required a lumbar drainage. Group 2 (collagen fleece, n = 6)): no case of CSF leak occurred, and 1 patient required a lumbar drainage. Group 3 (fi brin sealant + collagen fleece, n = 13) No CSF leak occurred in the postoperative course and no case required a lumbar drainage No safety data reported These data seem to con firm the synergistic action of the 2 materials (fi brin sealant + collagen fleece in assuring a safer and effective sellar repair in case of an intraoperative CSF leak 4 (Continued )
Table 5. (Continued ) Author, year Study design Intervention comparison Population Total number of patients Patients exposed to fi brin sealant Ef fi cacy (primary endpoint in bold if stated in paper) Safety Author conclusions Evidence level Seda 2006 [ 38 ] Case series Group 1 (no intraoperative CSF leak): Surgicel. Group 2 (intraoperative CSF leak): Surgicel + fibrin sealant (Beriplast) Patients undergoing reconstructing the sellar floor after transsphenoidal procedures 567 64 Group 1: No delayed CSF leak, meningitis, or visual loss. Group 2: 1/63 (1.6%) disclosed a delayed postoperative CSF leak treated by reoperation Group 1: No meningitis, or visual loss. Group 2: 1/64 patient developed meningitis but no overt CSF leak, treated by antibiotics Sellar floor closure with Surgicel and fibrin sealant without grafting/use of implants is a safe and ef ficient method to prevent postoperative complications after trans-sphenoid al procedures 4 Esposito 2008 [ 10 ]; Esposito 2013 [ 11 ] Prospective case series Collagen based dural replacement covered with fibrin sealant (Tisseel) No comparison Patients undergoing a variety of neurosurgical procedures (cranial, transsphenoidal, spinal) and requiring a dural graft implant. In a later publication 111 patients underwent follow up evaluation 5 years after surgery [ 11 ] 208 (111 at 5-year follow-up) 208 1/208 patients (0.5%) experienced postoperative CSF. Postoperative magnetic resonance imaging showed signs of moderate in flammatory response in only one patient, who did not present any postoperative clinical symptom nor neurological de ficits In 3 patients undergoing reoperation the dural substitute appeared to have promoted a satisfactory dural regeneration (histology). No or minimal adherences with the other tissues and the brain cortex. At 5 years follow up, 5 patients (4.5%) had undergone reoperation and 2 out of 5 experienced subcutaneous fluid collections The collagen-only biomatrix is a safe and effective dural substitute for routine neurosurgical procedures used together with fibrin sealant. Data are supported by a 5 year follow survey 111 patients 4 Cappabianca 2006 [ 7 ] Case series Collagen foil + fibrin sealant (Tisseel). No comparison Patients undergoing endoscopic endonasal transsphenoidal surgery for a variety of pituitary lesions. Patients with intraoperative CSF leaks or who needed sella floor reconstruction received the intervention (n = 15) 72 15 15/72 patients (20.8%) required implant of the collagen foil. 9/15 (60%) had intraoperative CSF leak. 1/15 (6.7%) developed postoperative CSF leak 1/15 (6.7%) presented with meningitis. The patient required a reoperation for CSF fistula repair and intravenous antibiotics. No other adverse events observed This experience suggests that the use of Collagen foil + fibrin sealant in trans-sphenoid al surgery is safe and biocompatible 4 Parlato 2011 [ 39 ] Case series Overlay with collagen foil + fibrin sealant (no dural sutures). No comparison Patients undergoing cranial and spinal procedures with the need of dural reconstruction 74 74 Clinical and neuroradiologic al (magnetic resonance scan at 1 week, 1 month and 1 year) findings were normal. No graft rejections or CSF leak were observed At 12 months follow-up, no local toxicity or complications such as CSF leaks, adherences or in flammation were observed. No further adverse events reported Following dural reconstructions with collagen foil + fibrin sealant without surgical sutures, no local toxicity or complications were observed for up to 1 year 4 (Continued )
Table 5. (Continued ) Author, year Study design Intervention comparison Population Total number of patients Patients exposed to fi brin sealant Ef fi cacy (primary endpoint in bold if stated in paper) Safety Author conclusions Evidence level Gazzeri 2009 [ 40 ] Prospective case series Collagen biomatrix + fibrin sealant (Tissucol); No comparison Patients > 18 years of age with cranial or spinal dural defect requiring placement of a dural substitute with a life expectancy > 6 months. Exclusion criteria: internal or external CSF shunt, known or suspected systemic or local infection, known systemic collagen disease, usage of corticosteroids, previous radiotherapy or chemotherapy 60 60 56 patients had cranial surgery, 4 had a spinal operation. At 7-days follow-up, 2/60 (3.3%) had CSF leak. Neither patient needed reoperation. A subgaleal fluid collection in two patients resolved after tapping. Of the 56 patients who reached the 3-month follow-up, none had a CSF leak Of the 56 patients who reached the 3-month follow-up, none developed meningitis, wound infection or CSF fistulae. No other adverse events reported The use of fibrin sealant reduces suturing and facilitates the implantation of the collagen biomatrix 4 Murai 2013 [ 41 ] Retrospective case series Sutures + Gelfoam + fibrin sealant. No comparison Fifty-one consecutive patients (age 15 – 71) undergoing bifrontal craniotomy with frontal sinus exposure for frontal base lesions. Patients without exposure of bony frontal sinus or the mucous membranes of frontal sinus were excluded 51 51 Postoperative CSF leakage: 0 with a postoperative follow-up period of 1– 84 months (mean: 36.8 months) No meningitis and no other adverse events reported during follow up The use of Sutures + Gelfoam + fibrin sealant indicates effectiveness in the prevention of frontal sinus related postoperative complications 4 Cappabianca 2010 [ 42 ] Case series Fibrin sealant (Tisseel) inside tumor cavity to fill dead space + other materials. No comparison 40 subjects undergoing endoscopic endonasal approach for different sellar and skull base lesions in which an intraoperative CSF leakage was evident 40 40 No postoperative CSF leaks No adverse events reported The injection of fibrin sealant proved to be effective in filling/ sealing postoperative “dead spaces ” and treating minor or initial CSF leaks 4 Van Velthoven 1991 [ 43 ] Case series Septal bone + fibrin sealant (Beriplast / Tissucol) + Spongycel for reconstruction of the sellar floor and sphenoid sinus. No comparison Patients undergoing transsphenoidal (sublabial, transseptal) operations due to a variety of sellar pathologies 119 119 Overall incidence of postoperative rhinorrhea was 1.6%. Intraoperative CSF leakage occurred in 15/119 (12.6%) of cases. Postoperative rhinorrhea occurred and persisted in 2 o f the 15 patients with intraoperative CSF leakage. None of the 104 patients without intra-operative CSF leakage developed postoperative rhinorrhea One patient suffered postoperative meningitis, associated with intra-operative and postoperative CSF leak treated with antibiotics, no sequelae. One patient developed hepatitis A — unrelated to the use of fibrin sealant This supports the view that sellar and sphenoidal sealing with fibrin sealant instead of muscle or fat tissue does not raise the incidence of post-operative rhinorrhea 4 (Continued )
Table 5. (Continued ) Author, year Study design Intervention comparison Population Total number of patients Patients exposed to fi brin sealant Ef fi cacy (primary endpoint in bold if stated in paper) Safety Author conclusions Evidence level Yin 2005 [ 44 ] Retrospective case series 4 techniques were evaluated: 1. Gelatin foam; 2. Gelatin foam + fibrin sealant; 3. Gelatin foam + fibrin sealant + autologous fat; 4. Regimen 1, 2, or 3 + CSF drainage Consecutive patients age 13 – 72, undergoing sellar floor reconstruction following transsphenoidal surgery 176 77 Patients developed postoperative CSF leaks in 0, 0, 1.6%, and in 0% of the cases (tech. 1,2,3,4, respectively). Magnetic resonance imaging follow-up after 12 months showed progressive resorption of material in sella No postoperative complications such as CSF rhinorrhea, allergic rhinitis, meningitis, or pneumocranium and no deaths Gelatin foam and fibrin sealant in cranial reconstruction is safe and effective in preventing
postoperative complications following
trans-sphenoidal surgery 4 Jankowitz 2009 [ 45 ] Retrospective case series Suture + fibrin sealant (Tisseel) versus suture alone Patients undergoing lumbar spine surgery experiencing an incidental durotomy 4835 278 Incidental durotomy occurred with an overall incidence of 11.3%. Fibrin sealant was used during 278 of these cases (50.8%) to augment the dural closure. 31/269 (11.5%) without fibrin sealant developed CSF leak vs. 33/278 (11.9%) with fibrin sealant (not signi ficant). Logistic models evaluating age, sex, redo surgery, and the use of fibrin sealant revealed that prior lumbar spinal surgery was the only univariate predictor of persistent CSF leak, conferring a 2.8-fold increase in risk There were no complications associated with the use of fibrin sealant In patients who experienced an incidental durotomy during lumbar spine surgery, the use of fibrin sealant for dural repair did not signi ficantly decrease the incidence of a persistent CSF leak 4 Kassam 2003 [ 46 ] Retrospective case control (historical) study Suture + fibrin sealant (Tisseel) versus suture Patients undergoing anterior cranial base, infratemporal, and retromastoid surgical procedures 253 72 10/181 (5.5%) control patients versus 0% fibrin sealant treated patients developed postsurgical CSF leaks (p = 0.067). In patients undergoing anterior cranial base procedure, CSF leaks occurred in 16 versus 0%, (control versus fibrin sealant) 1.1% of controls versus 0 developed pneumocranium (control versus fibrin sealant, respectively). No further adverse event data available Fibrin sealant reduces the incidence of postoperative CSF leaks and tension pneumocranium 4 Kurschel 2007 [ 47 ] Retrospective case series Mixture of fibrin sealant (Beriplast) and Surgicel Endoscopic third ventriculostomies were performed in 20 hydrocephalic children with a mean age of 22 months 20 20 One child developed an asymptomatic CSF leak that was managed conservatively . The leak was attributed to the age of the child and assumed poor CSF absorption ability No adverse effects regarding the material used for sealing were observed over a mean follow-up of 23 months Fibrin sealant and Surgicel seems to be safe, and this technique effectively in reducing the risk of CSF leaks in this patient population 4 (Continued )
Table 5. (Continued ) Author, year Study design Intervention comparison Population Total number of patients Patients exposed to fi brin sealant Ef fi cacy (primary endpoint in bold if stated in paper) Safety Author conclusions Evidence level Parker 2011 [ 48 ] Retrospective case series Sutures + different graft types (cadaveric pericardium, Durepair, and EnDura) augmented with either: 1. No sealant; 2. Fibrin sealant (Tisseel); 3. Duraseal (PEG matrix) Consecutive patients 18 years old undergoing primary Chiari malformation Type I decompression using duraplasty 114 75 Fibrin sealant was used in 75 patients, DuraSeal in 12, and no tissue sealant was used in 27 patients. No ef ficacy data presented The overall complication rate was 21.1% (aseptic meningitis, pseudo-meningocele, or a CSF leak requiring reoperation). Complication rates for tissue sealants were 14.8% for no sealant, 18.7% for fibrin sealant, and 50% for DuraSeal (p < 0.05). A subgroup treated with Durepair and DuraSeal had a 56% complication rate. Cases of aseptic meningitis were linked to one graft (Durepair) The use of tissue sealants to augment duraplasty may not provide any additional bene fit 4 Gazzeri 2011 [ 49 ] Case series Oxidized cellulose for dura defect + fibrin sealant (Tissucol). No comparison Patients either scheduled (n = 21) or emergency (n = 24)
undergoing supratentorial craniotomies
with dural defects ranging from 10 – 40 mm (min-max) 467 45 Postoperatively, 3/45 (6.7%) developed subgaleal fluid collection, which resolved conservatively in 2 cases There were no other complications or reoperations Oxidized cellulose + fibrin sealant, is a sutureless, fast, and valid alternative to small dural defect closure methods 4 Gillman 1995 [ 50 ] Retrospective case series Fibrin sealant (Tisseel) indural closure in translabyrint hine resection. No comparison Patient undergoing surgical and non-surgical treatment for acoustic neuroma 83 52 Postoperative CSF leaks in 6/52 (11.5%) of patients treated with fibrin sealant undergoing translabyrint hine resection No safety data reported Further randomized controlled trials to evaluated fibrin sealant for CSF leaks are merited 4 Hida 2006 [ 51 ] Prospective case series Polyglycoic acid (PGA) sheet + fibrin sealant (Bolheal). No comparison Patients undergoing spinal surgery requiring intraoperative dura repair 160 160 Postoperative subcutaneous CSF accumulation occurred in 10/160 (6.3%) cases No complications such as allergic reaction, adhesion, or infection The polyglycoic acid-fibrin sealant sheet is a viable alternative method for dural repair in spinal surgery 4 (Continued )
Table 5. (Continued ) Author, year Study design Intervention comparison Population Total number of patients Patients exposed to fi brin sealant Ef fi cacy (primary endpoint in bold if stated in paper) Safety Author conclusions Evidence level Reddy 2002 [ 52 ] Retrospective case series Fibrinogen / thrombin based collagen fleece (Tachocomb). No comparison Consecutive patients undergoing neurosurgical and spinal procedures (intracranial tumors, cerebellar tumors, traumatic lesions, spinal lesions, microvascular decompression for trigeminal neuralgia, vascular diseases, infections)All patients, in whom a primary dural closure or a watertight closure was not possible and in whom autograft harvest was either impractical or impossible were considered eligible 288 288 Postoperative CSF leaks developed in 5/288 (1.7%) patients, requiring reoperation. Rebleeding observed in 1 patient. In 4/288 (1.4%) patients, there was notable subcutaneous CSF accumulation without CSF-leak requiring lumbar drainage No super ficial or deep wound infections or aseptic meningitis were noted. No other adverse events reported Fibrin sealant based-collagen fleece is an adequate alternative for dural substitution: it is safe, watertight and ef ficient 4 Reddy 2003 [ 53 ] Retrospective case series Fibrin sealant based collagen fleece (Tachocomb). No comparison 421 brain surgery cases, 42 of which involved the skull base 421 421 12/421 (2.8%) developed postoperative subcutaneous CSF leak. 3 patients required reoperation No safety data reported. Fibrin sealant based collagen fleece is watertight and effective 4 Nistor 1997 [ 54 ] Case series Fibrin sealant based collagen fleece (Tachocomb). No comparison Patients undergoing neurosurgical intervention for primary skull base pathology 44 44 0 postoperative CSF leaks with a mean follow up time of 18 months No cases of meningitis during a median follow-up period of 18 monthsPostoperative magnetic resonance imaging did not reveal any CSF or infectious abnormalities. One case of pneumocephalus Experience from this case series shows good sealing performance of fibrin sealant based collagen fleece used in skull base surgery 4 Cho 2011 [ 55 ] Retrospective case series Intraoperative CSF leaks repaired with fibrin sealant-base d collagen fleece (TachoComb). No comparison Patients undergoing transsphenoidal surgery for pituitary adenoma (Hardy grade I-IV) experiencing intraoperative CSF leak 307 90 2/90 (2.2%) patients developed postsurgical CSF leak (rhinorrhea) No hypersensitivity reactions against fibrin sealant and no infections within 16 months of follow-up (magnetic resonance imaging) This technique is an alternative method to the traditional autologous tissue graft technique 4 Black 2002 [ 56 ] Retrospective case series Fat + fibrin sealant + Gelfoam/ Surgicel applied to spinal dural tear. No comparison Patients undergoing spinal surgery for various pathologies where unintended spinal tears occur 1650 27 Of 27/1650 unintended dural tears, 1/27 (3.7%) developed postoperative CSF leak treated with skin suture No safety events reported The use of a fat graft is recommended as a rapid, effective means of prevention and repair of CSF leaks following spinal surgery 4 (Continued )
Table 5. (Continued ) Author, year Study design Intervention comparison Population Total number of patients Patients exposed to fi brin sealant Ef fi cacy (primary endpoint in bold if stated in paper) Safety Author conclusions Evidence level Weber 1996 [ 57 ] Retrospective survey Endonasal duraplasty, external duraplasty (frontoorbita l o r transfrontal extradural approach) by underlay/onlay technique. Fibrin sealant (Tisseel) used to seal grafts of mucosal flaps. No comparison Consecutive sample of patients undergoing duraplasty for repair of a dural lesion that occurred as a complication of endonasal sinus surgery 47 47 42 patients were followed up 5 years after surgery (range: 6 month to 15 years). Fluorescein test, performed in 43% (20/47) of the patients was negative in all case. Duraplasty was clinically intact in 100% 26% of the patients had had 1 o r more episodes of bacterial sinusitis. No cases of CSF rhinorrhea or meningitis Allogeneic connective tissue in combination with fibrin sealant has proved suitable as a graft material 4 Treatment of persisting CSF leaks Cassano 2009 [ 58 ] Retrospective case series Overlay apposition of a lower turbinate mucoperiostal graft fixated with fibrin sealant and Surgicel. No comparison Adults undergoing anterior skull base repair of persisting CSF fistulae treated endoscopically using overlay apposition of graft + fibrin sealant + Surgicel 125 125 The success rate at first attempt was 94.4% There were 7/125 (5.6%) cases of postoperative recurrent CSF leakage (all resolved at 3 month follow-up) No safety data reported Repair of anterior skull base CSF fistulae with the described technique with fixators (fi brin sealant) and supports (Surgicel, Spongostan), permits the restoration of dural continuity in a majority of cases 4 Cappabianca 2010 [ 42 ]* Case series Fibrin sealant (Tisseel) locally injected with application system/ Tuohy needle every 48 hours until CSF leak treated. No comparison 10 subjects with postoperative CSF leakage after transsphenoidal, spinal, posterior fossa and transcortical transventricular tumour removal surgery 10 10 All CSF leaks or collections were closed after 1 to 5 applications of fibrin sealant. Successful results were stable with a follow-up ranging from 6 months to 3 years No adverse events reported The injection of fibrin sealant may add another possibility in the treatment of post-operative CSF leaks 4 * Th ese 10 patients were a subpo pulation am ong th e 5 0 patients in the Ca ppabian ca cas e series publi cation [ 42 ]. Note: Fibrin seal ant brand name inclu ded if cited in public ation. CSF = cer ebrospin al fluid doi:10. 1371/journal.pone.0151533.t005
indication of suture line sealing in dura mater closure. Among the 139 patients evaluated, fibrin
sealant was used as an adjunct to sutures in 89 patients with the remaining“control group”
participants managed through the use of additional sutures. The primary endpoint was the per-centage of patients attaining intraoperative watertight dura closure. This endpoint was met in 92.1% of fibrin sealant managed patients and 38% of those managed with additional sutures (p<0.001). This significant difference in intraoperative CSF leaks had no effect on the fre-quency of postoperative leaks, which occurred in 6.7% of fibrin sealant patients and 2% of the additional suture control group. Adverse event incidence rates were similar between the groups and there was no increased occurrence of safety events in those exposed to fibrin sealant. The findings of this Evidence Level 1b, well-designed, randomized controlled trial supports the effi-cacy and the safety of fibrin sealants over additional sutures in attaining intraoperative dura sealing.
In an Evidence Level 4, retrospective case series of 120 patients undergoing pituitary
sur-gery, fibrin sealant was used with different materials to pack the sphenoid sinus [22]. The
intraoperative leak rate was 3.6% and a single case of aseptic meningitis was reported. Limita-tions in the study design preclude firm efficacy and safety conclusions from this analysis.
Prevention of Postoperative CSF leaks. A randomized controlled pilot trial identified
only on the clinicaltrials.gov website provided Evidence Level 1b on the use of liquid fibrin
seal-ant in the prevention of postoperative CSF leaks in patients undergoing cranial surgery [29]. In
the 62 patients enrolled, the dura mater was closed with sutures and patches (standard of care) alone or with liquid fibrin sealant used as an adjunct. The primary endpoint, the prevention of postoperative CSF leaks, was compared between those treated with standard of care alone and those who received fibrin sealant adjunct management. The endpoint was evaluated clinically and with extensive computed tomography and magnetic resonance imaging techniques (CT/ MRI) at 33 days and 5 weeks postoperatively. At the first postoperative evaluation (33 days), the percentage of patients with postoperative CSF leaks was similar between the groups (78% in fibrin sealant adjunct and 74% in standard of care alone group). Safety events, including
Table 6. Appraisal of Study Quality for Three Randomized Controlled Trials*. Study Primary outcome stated? Inclusion / exclusion specified †Generation of allocation sequence adequate? †Allocation concealment adequate? a priori sample size/ power calculation Blinded outcome assessors? Blinded patients? Consecutive cases? Intent-to-treat analysis Lost to follow up (%) Green 2014 [24]
Yes Yes Unclear Unclear Yes No Yes Yes Yes (1–2%)
Clinicaltrials. gov NCT 00681824
[29]
Yes Yes Unclear Unclear No Yes Yes Yes Yes 0
Nakamura 2005 [32]
Yes Yes No No Yes#1 No Unclear Yes No 0
Possible answers for each section are: Yes (low risk of bias [ROB]), No (high ROB) and Unclear (Uncertain ROB). Unclear denotes where there is insufficient information in the publication to permit a clear judgment).
ITT = intent to treat.
*Inspired by the risk of bias table (Figure 8.6.a) in Higgins JPT, Altman DG (Eds). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (Eds). Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2008. Availablwww.cochrane-handbook.org
[59].
†The minimum criteria for adequate concealment are based on data from Schultz and Grimes, 2002 [60]. #1: Sample size done, reported but not followed in actual study.
surgical revisions and infections, were distributed evenly in the two groups. The findings of this trial do not establish the prevention of CSF leaks with fibrin sealants, but did report a com-parable safety profile between the sutures and patches standard of care and the use of fibrin sealant as an adjunct.
A smaller (39 patients) randomized controlled trial provided Evidence Level 2b on the effi-cacy of liquid fibrin sealant adjunct to sutures and Goretex in the closure of spinal cord dura
[32]. As mentioned previously, this study by Nakamura and colleagues had several
design-related quality issues that limit the interpretation of their findings such as use of a pseudo ran-domization system, an a priori sample size, and the potential for being underpowered and
biased [32]. In the study, postoperative CSF leakage was the secondary endpoint with the
pri-mary endpoint being haemostasis. CSF leakage postoperatively was not observed in any of the study patients and no adverse events or complications were reported. Although not statistically significant, the data demonstrates that fibrin sealants were effective in preventing postoperative CSF leakage in the patients evaluated.
Three studies used a case control design [33–35] to assess fibrin sealants in preventing CSF
leaks. In a study of 200 patients undergoing fossa posterior surgery with intraoperative CSF
leaks, Than and colleagues [33] compared the use of fibrin sealants with PEG sealant. Overall,
10% of those exposed to fibrin sealants and 2% of those in the PEG group developed a
postop-erative CSF (p = 0.03). Yoshimoto and colleagues [35] compared treatment with a liquid fibrin
sealant with sutures versus sutures alone (control group) in preventing postoperative CSF leaks in 183 patients undergoing craniotomy. The incidence of postoperative CSF leaks, verified by computed tomography, was 26% in the fibrin sealant group and 42% in the control group
(p>0.05). Tamasauskas and colleagues [34] also used a case controlled approach to evaluate
the incidence of postoperative CSF leaks in patients undergoing transsphenoidal surgery for pituitary adenoma with intraoperative detected CSF leaks. Intraoperative CSF leaks were treated with packing of the sella and sphenoidal sinus with different materials with a dry patch fibrin sealant or without (control group). No fibrin sealant-managed patient and 10% of those not managed with fibrin sealant developed a postoperative CSF leak. In these three case
con-trolled trials [33–35], safety was reported to occur with a similar distribution between the fibrin
sealant and control groups. In such trials where there is a high risk of bias that may influence the interpretation of efficacy and safety results, no consistency was shown of fibrin sealant effi-cacy and no safety issues were identified (Evidence level 3).
The majority of the selected papers reported data from case series that were either prospec-tive or retrospecprospec-tive. In total, 22 such papers were selected with 2 papers reporting follow-up
on same patient cohort [10,11]. In these analyses, fibrin sealants were used predominantly in
cranial procedures [10,11,39,40,41,46,48,49,52,54] with low incidences (0 to 6.7%) of
post-operative CSF leaks reported. In one case series where fibrin sealant was used in a subgroup of patients undergoing surgical treatment for acoustic neuroma with translabyrinthine resection,
11.5% of patients experienced postoperative CSF leak [50]. Fibrin sealant was reported to be
effective, with postoperative CSF leaks rates of 0 to 6.7%, in patients undergoing
transsphenoi-dal surgery [7,37,38,42,43,44,55,57].
The use of fibrin sealant was assessed in 2 papers in patients undergoing transsphenoidal
surgery. In the retrospective analysis by Cappabianca and colleagues [37], 2 of 16 patients
(12.5%) treated with fibrin sealant alone presented with a postoperative CSF leak compared to none of the patients who received a fibrin sealant/collagen fleece combination. In the
consecu-tive patient analysis by Yin and colleagues [44], the 77 patients who developed a visible
intrao-perative CSF leak were repaired with fibrin glue plus gelatin foam (n = 62) or with autologous fat graft and sellar floor reconstruction (n = 15), with the authors concluding that the use of
fibrin glue with gelatin foam was effective and safe in preventing postoperative complications following transsphenoidal surgery.
In a small case series of 20 children with hydrocephalus where fibrin sealant was used, one
child (5%)) developed a CSF leak [47]. In three case series of patients undergoing spinal surgery
with dural repair where fibrin sealant was used to enforce the dural suture line, between 3.7%
to 11.9% of patients developed postoperative CSF leak [45,51,56]. In general, in these case
series, safety events occurred infrequently (meningitis, pseudomeningocele, pneumocephalus, seeTable 5for details). The results from these case series are limited in their interpretation on safety and efficacy due to design (Evidence level 4).
In two retrospective case series an attempt was made to compare the effect of fibrin sealant
to a control in the incidence of persistent CSF leakage [45,48]. In the analysis by Jankowitz
[45] of 547 patients undergoing lumbar surgery and experiencing incidental durotomy during
the first 3-month postoperative period, a total of 64 patients (11.7%) experienced a persistent CSF leak. There was no difference in the percentage of patients who experienced a persistent CSF leak in which fibrin glue was used to augment the dural closure (11.9%, n = 33) and those
in which fibrin glue was not used (11.5%, n = 31) [45]. In a study by Parker and colleagues [48]
of 114 consecutive children undergoing primary Chiari I malformation Type I decompression using duraplasty, the complication rate for tissue sealants was 14.8% in the 27 patients man-aged with no sealant and 18.7% for the 75 patients manman-aged with fibrin sealant. The findings of
these two studies [45,48] indicate that there is no additional benefit of fibrin sealant use over
other procedures; however, the retrospective case series design limits the ability to draw firm conclusions from these data.
Treatment of Persisting CSF leaks. Two case series reported the experience of treating
patients with persisting CSF leaks after a variety of surgical intervention types (skull base,
spi-nal, posterior fossa and other) [42,58]. In the larger series of 125 patients by Cassano and
col-leagues [58], fibrin sealant used with turbinate grafts and Surgicel resulted in a postoperative
recurrent CSF leakage rate of 5.6%. In the smaller case series of 10 patients who underwent dif-ferent neurosurgical procedures and developed postoperative CSF fistulas or collection, the
local injection of fibrin sealant was effective in treating the complication [42]. Among the 10
patients, 4 had undergone transsphenoidal surgery, 2 had undergone spinal surgery, 3 under-went posterior fossa surgeries and one underunder-went transcortical transventricular tumour
removal. In this study by Cappabianca 2010 and colleagues [42], the liquid fibrin sealant
cations were repeated every 48 hours until the disappearance of the leak. The number of appli-cations ranged from one to five, with the application being successful in all cases. No adverse events were reported in these studies. The results from these case series are limited in their interpretation on safety and efficacy due to the reported design (Evidence level 4).
Results for Safety Evaluation Based on Specific Reported Adverse Events. As
summa-rized inTable 5, few or no adverse events were reported in most of the studies. In the three
ran-domized controlled trials where there is a specific comparison of treatment with and without
fibrin sealants [24,29,32], no increased adverse events due to fibrin sealants was detected
(Table 5).
Table 7presents an overview of specific adverse events reported in publications that reported on the safety of fibrin sealants used in or near dura mater. From 1987, when the first
safety case was reported, until 2014 there have been a total of 8 cases in neurosurgery [61–67].
These 8 cases included 2 allergic reactions [61,65], 3 cases of aseptic meningitis [66,67], one
case of meningitis with fatal outcome with only limited information provided in the paper
[62], one case of suspected air embolism with the use of a spray device [63], and one case of
obstruction of epidural drain [64]. One of the 2 allergic reactions was supported by the finding
Table 7. Literature Search: Specific Reported Adverse Events, in Alphabetical order by first author.
Author, year Report type Adverse event reported and incidence Comments Beierlein,
2000 [61]
Case report 48 year old woman developed a liquidfistula after cranial surgery for cerebral metastasis. 29 days postsurgery, 4 mlfibrin sealant (Tissucol) was injected into subgaleal cavity. 40 days postsurgery another 4 ml offibrin sealant was injected followed by clinical signs of anaphylactic shock. Serology identified aprotinin specific IgE and IgG.
Serology confirmed. Aprotinin is a bovine protein and as such is a potential allergen.
Czepko, 2006 [62]
Single case report
Limited information from abstract in English: 259 consecutive cases performed using a transsphenoidal approach. Intraoperative rhinorrhea occurred in 40 cases wherefibrin sealant was used in sella reconstruction. Twenty-six (26) cases (group I) received Surgicel, artificial dura or fascia and fibrin sealant (Tissucol) and 14 cases (group II) received TachoComb +fibrin sealant, fascia or artificial dura. One patient died due to the meningitis (group I). No further information is available and no causality is given.
Very limited information and no causality tofibrin sealant given.
Felema, 2013 [63]
Case report A 5-month old, Ex-33-week premature, 6.6-kg male scheduled for endoscopic cranial vault remodeling for sagittal craniosynostosis. At the completion of the surgical procedure and prior to skin closure, 4 ml offibrin sealant (Tisseel) was applied for haemostasis at an approximate distance of 5 cm from the anterior endoscopic entrance site using an aerosolized spray applicator device (Easyspray) with nitrogen as a propellent gas at a pressure of 15 psi. Immediately afterfibrin sealant delivery, a sudden drop in blood pressure from 88/42 to 38/21 was noted lasting 5 min. with no perceived change in blood loss. It was hypothesized that air was introduced to the vascular system with the spray device.
Causality tofibrin sealant only a hypothesis. Tisseelfibrin sealant has a special warning and precaution in Summary of Product Characteristics for use with gas and in confined spaces.
Handa, 1989 [64]
Case report In an observational studyfibrin sealant (Beriplast B) was used in 48 places, at 36 neurosurgical operations in 34 patients. In one case wherefibrin sealant was applied over the dural surface, obstruction of an epidural drain occurred resulting in an epidural haematoma (no further details in abstract).
Spray directly on drain potential obstruction.
Kanazawa, 2010 [65]
Case report A 65 year old woman underwent surgical craniotomy where arachnoid plasty withfibrin sealant (Beriplast) was completed. Nine days post-surgery the patient underwent abrupt neurological deterioration. Neuroimaging and clinicalfindings indicated allergic reaction that was successfully treated with steroids. It was hypothesized that components in thefibrin sealant led to the observed allergic reaction.
Causality tofibrin sealant only a hypothesis.
Schlenker, 1987 [66]
Controlled trial. One case report
This controlled trial evaluatedfibrin sealant (Tissucol) for the prevention of post lumbar puncture headache. Following lumbar puncture, patients were treated withfibrin sealant injected through lumbar needle immediately after dural tap. Thefirst 6 patients were treated uneventfully. The 7th patient, a 58 year old female, developed aseptic meningitis treated with antibiotics. Allergy test forfibrin sealant components were negative. No evidence of contamination of trial product. The author suspected chemical irritation caused by component of thefibrin sealant could not be excluded.
Causality tofibrin sealant only a hypothesis.
Wakamoto, 2002 [67]
2 Case reports Limited information from abstract in English: A 56 year old female undergoing microvascular decompression. Eighteen days after procedure the patient was diagnosed with aseptic meningitis. A 30 year old male experienced the same symptoms 15 days after same surgery. Dacron, Goretex and Lyodula were used together withfibrin sealant, the latter to prevent CSF leak. It was suggested that the humanfibrinogen was the cause of the aseptic meningitis that was successfully treated with steroids.
Causality tofibrin sealant only a hypothesis.
allergic reaction would have been observed if the product was applied topically, rather than sys-temic. The second allergic reaction, like most reported reactions was not confirmed as directly
related to the product, but could be possibly related [61].
When evaluating safety in these complex interventions and in patients with potential comorbidities, it is important to take into consideration the fact that a number of other prod-ucts, including fibrin sealant, are used during these procedures. As such, direct determination of causality is difficult. Overall the specific adverse events are few and not frequently reported over a period of more than 25 years.
Discussion
Cerebrospinal fluid does not forgive and a careless dural closure almost certainly will result in a leak. For the surgeon, cerebrospinal fluid leaks are a frustrating complication of neurosurgical procedures, while for the patient these can result in unanticipated morbidity and mortality. Like most complications, cerebrospinal fluid leaks are best managed by prevention of their occurrence. During recent decades, dural closure after routine and emergency neurosurgical procedures has been performed with the use of suitable autologous, heterologous, or many dif-ferent synthetic materials, and also with biological, semisynthetic, or synthetic glues. Such materials have been used individually or combined according to different techniques reported in the literature.
The introduction of fibrin sealants has resulted in the rate of postoperative CSF leakage being dramatically reduced thus reducing also the costs related to the management of CSF leak complications and the length of postoperative hospitalization. Fibrin sealants are widely used for a variety of neurosurgical indications such as dural closure and/or reinforcement
With this systematic literature review we aimed to evaluate the evidence available in the lit-erature and relate it to our experience with fibrin sealants in neurosurgery. Our goal was to evaluate whether the clinical clinical data for fibrin sealants support their use in dura sealing, either to prevent acute CSF leaks (perioperatively) in patients after neurosurgery or to prevent/ treat persistent CSF leaks (postoperatively or with instrumentation) with regards to efficacy and safety of the products. This extensive literature search identified only a few randomized clinical trials that provide a high level of evidence regarding the efficacy and safety of fibrin sealants used for these indications. The literature search identified several lower quality studies including case series and reports that were included in our analysis, with these representing the majority of studies evaluated and a limitation to the conclusions that may be drawn from the findings.
In this systematic review the best quality study was a large randomized controlled trial that evaluated the perioperative application of fibrin sealants directly to the suture line to stop acute CSF leaks in patients undergoing neurosurgical procedures. The definition of a perioperative acute CSF leak is straightforward and simple and evaluated on the spot by the neurosurgeon. In the largest randomized controlled trial identified in this review, liquid fibrin sealant was applied directly to the suture line with a clear superior efficacy as it provided watertight closure
of the durotomy in 92% versus 28% in the suture only group [29]. This feature allows the final
closure of patient and perhaps a reduced surgical time, however this is not supported by the available data. However, these findings were not consistent with a reduced frequency of post-operative clinically relevant CSF leaks.
The definition of postoperative CSF leaks varied widely from extensive use of radio imaging
with the identification of even small non clinically relevant fluid accumulations [29] to only
evaluating clinical relevant CSF leaks (most of the reported studies). The clinical relevance of evaluating the effect of fibrin sealants on fluid accumulations detected with imaging such as
